Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition

Bram Priem, Mandy M T van Leent, Abraham J P Teunissen, Alexandros Marios Sofias, Vera P Mourits, Lisa Willemsen, Emma D Klein, Roderick S Oosterwijk, Anu E Meerwaldt, Jazz Munitz, Geoffrey Prévot, Anna Vera Verschuur, Sheqouia A Nauta, Esther M van Leeuwen, Elizabeth L Fisher, Karen A M de Jong, Yiming Zhao, Yohana C Toner, Georgios Soultanidis, Claudia CalcagnoPaul H H Bomans, Heiner Friedrich, Nico Sommerdijk, Thomas Reiner, Raphaël Duivenvoorden, Eva Zupančič, Julie S Di Martino, Ewelina Kluza, Mohammad Rashidian, Hidde L Ploegh, Rick M Dijkhuizen, Sjoerd Hak, Carlos Pérez-Medina, Jose Javier Bravo-Cordero, Menno P J de Winther, Leo A B Joosten, Andrea van Elsas, Zahi A Fayad, Alexander Rialdi, Denis Torre, Ernesto Guccione, Jordi Ochando, Mihai G Netea, Arjan W Griffioen, Willem J M Mulder

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

Original languageEnglish
Pages (from-to)786-801.e19
JournalCell
Volume183
Issue number3
DOIs
Publication statusPublished - 29 Oct 2020

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